Application of film-casting technique to investigate drug-polymer miscibility in solid dispersion and hot-melt extrudate.

Determination of drug-polymer miscibility is critical for successful development of solid dispersions. This report details a practical method to predict miscibility and physical stability of drug with various polymers in solid dispersion and, especially, in melt extrudates by applying a film-casting technique. Mixtures of itraconazole (ITZ) with hydroxypropylmethylcellulose phthalate (HPMCP), Kollidon(®) VA 64, Eudragit(®) E PO, and Soluplus(®) were film-casted, exposed to 40°C/75% RH for 1 month and then analyzed using differential scanning calorimetry (DSC), powder X-ray diffractometry, and polarized light microscopy (PLM). ITZ had the highest miscibility with HPMCP, being miscible at drug to polymer ratio of 6:4 (w/w). There was a downward trend of lower miscibility with Soluplus(®) (miscible at 3:7, w/w, and a few microcrystals present at 4:6, w/w), Kollidon(®) VA 64 (2:8, w/w) and Eudragit(®) E PO (<1:9, w/w). PLM was found more sensitive to detect drug crystallization than DSC and powder X-ray diffractometry. There was general correlation between results of film casting and hot-melt extrusion (HME) using a twin screw extruder. For ITZ-Soluplus(®) mixtures, HME at 4:6 (w/w) resulted in a single phase, whereas drug crystallization was observed at higher drug load. HME of ITZ-Kollidon(®) VA 64 mixtures also correlated well with the miscibility predicted by film casting.

Parikh T ，Gupta SS ，Meena AK ，Vitez I ，Mahajan N ，Serajuddin AT ... -  《-》

Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus(®) processed by hot melt extrusion.

The aim of this study was to evaluate a novel combination of hydroxypropyl methylcellulose phthalate (HPMCP-HP-50) and Soluplus® polymers for enhanced physicochemical stability and solubility of the produced amorphous solid dispersions (ASDs). This was achieved using hot melt extrusion (HME) to convert the crystalline active pharmaceutical ingredient (API) into a more soluble amorphous form within the ternary systems. Itraconazole (ITZ), a Biopharmaceutics Classification System class II (BCS II) API, was selected as the model drug. The ASDs were characterized by Powder X-Ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FTIR) spectroscopy, Solid State Nuclear Magnetic Resonance (ssNMR) and dissolution studies. The data showed that the ASDs were physically and chemically stable at 20°C and 50% RH over 12 months. PXRD results indicated that the ITZ in the ASDs was in the amorphous state and no recrystallization occurred. DSC scans confirmed that each formulation exhibited a single intermediate glass transition (Tg), around 96.4°C, indicating that ITZ was completely miscible in the polymeric blends of HPMCP and Soluplus® at up to 30% (w/w) drug loading and that the two polymers were miscible with each other in the presence of ITZ. The FTIR analysis indicated the formation of strong hydrogen bonding between ITZ, HPMCP and Soluplus®. The dissolution end-point of the ASDs was determined to be approximately 10 times greater than that of the crystalline ITZ.

Albadarin AB ，Potter CB ，Davis MT ，Iqbal J ，Korde S ，Pagire S ，Paradkar A ，Walker G ... -  《-》

Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination.

The purpose of this work was to increase the solubility and the dissolution rate of itraconazole, which was chosen as the model drug, by obtaining an amorphous solid dispersion by hot melt extrusion. Therefore, an initial preformulation study was conducted using differential scanning calorimetry, thermogravimetric analysis and Hansen's solubility parameters in order to find polymers which would have the ability to form amorphous solid dispersions with itraconazole. Afterwards, the four polymers namely Kollidon® VA64, Kollidon® 12PF, Affinisol® HPMC and Soluplus®, that met the set criteria were used in hot melt extrusion along with 25wt.% of itraconazole. Differential scanning confirmed that all four polymers were able to amorphize itraconazole. A stability study was then conducted in order to see which polymer would keep itraconazole amorphous as long as possible. Soluplus® was chosen and, the formulation was fine-tuned by adding some excipients (AcDiSol®, sodium bicarbonate and poloxamer) during the hot melt extrusion process in order to increase the release rate of itraconazole. In parallel, the range limits of the hot melt extrusion process parameters were determined. A design of experiment was performed within the previously defined ranges in order to optimize simultaneously the formulation and the process parameters. The optimal formulation was the one containing 2.5wt.% of AcDiSol® produced at 155°C and 100rpm. When tested with a biphasic dissolution test, more than 80% of itraconazole was released in the organic phase after 8h. Moreover, this formulation showed the desired thermoformability value. From these results, the design space around the optimum was determined. It corresponds to the limits within which the process would give the optimized product. It was observed that a temperature between 155 and 170°C allowed a high flexibility on the screw speed, from about 75 to 130rpm.

Thiry J ，Lebrun P ，Vinassa C ，Adam M ，Netchacovitch L ，Ziemons E ，Hubert P ，Krier F ，Evrard B ... -  《-》

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME.

Huang S ，O'Donnell KP ，Keen JM ，Rickard MA ，McGinity JW ，Williams RO 3rd ... -  《AAPS PHARMSCITECH》

Hot melt extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug-polymer interactions on supersaturation.

The processing parameters for HME have been evaluated and the impact of solid state intermolecular drug-polymer interactions on supersaturation has been investigated. Poorly water soluble drugs Indomethacin (IND), Itraconazole (ITZ), and Griseofulvin (GSF) and hydrophilic polymers - Eudragit EPO, Eudragit L-100-55, Eudragit L-100, HPMCAS-LF, HPMCAS-MF, Pharmacoat 603, and Kollidon VA-64 were selected for this study. Solubility parameters calculations (SPCs), differential scanning calorimetry (DSC), and rheological analysis of drug-polymer physical mixtures (PMs) was performed. The solid dispersions were manufactured using HME and characterized by powder X-ray diffraction (PXRD), polarized light microscopy (PLM), Fourier transform infra-red (FTIR) Spectroscopy, and dissolution study. Results obtained by DSC correlated well with SPC, showing single glass transition temperatures for all the PMs except ITZ in Eudragit EPO that depicted the highest difference in solubility parameters. The zero rate viscosity (η₀) was dependent on the melting point and consequently the state of the drug in the polymer at the softening temperature. The η₀ of PMs was useful to estimate the processing conditions for HME and to produce transparent glassy HMEs from most of the PMs. The amorphous conversion due to HME was confirmed by PXRD and PLM. The solid state drug-polymer interactions occurred during HME could be confirmed by FTIR analysis. Highest supersaturation could be achieved for IND, ITZ, and GSF using Eudragit EPO, HPMCAS-LF, and Eudragit L-100-55, respectively where relatively higher stretching of the carbonyl peaks was observed by FTIR. Thus, the highest dissolution rate and supersaturation of poorly water soluble drugs could be attributed to drug-polymer interactions occurred during HME.

Sarode AL ，Sandhu H ，Shah N ，Malick W ，Zia H ... -  《-》